Plasma ANGPTL7 Links Insulin Resistance to Heart Failure: Unveiling a Novel Fibro-Metabolic Axis in Type 2 Diabetes

Heart failure (HF) is a major cardiovascular complication of type 2 diabetes mellitus (T2DM), yet reliable biomarkers for early risk stratification remain limited. We investigated the prospective association between plasma angiopoietin-like protein 7 (ANGPTL7) and incident HF, and examined the extent to which this relationship is mediated by insulin resistance (IR).

This study included 2871 participants with T2DM and no baseline HF from the UK Biobank. Plasma ANGPTL7 was quantified using the Olink Proximity Extension Assay. Incident HF was ascertained via hospital and death records over a median follow-up of 13.5 years. Multivariable Cox proportional hazards models and restricted cubic splines (RCS) were employed to estimate hazard ratios (HRs) and evaluate dose-response relationships. Predictive performance was assessed using time-dependent receiver operating characteristic (ROC) curves. Furthermore, we conducted stratified analyses by HF polygenic risk score (PRS) and performed causal mediation analysis to quantify the contributions of IR indices.

Elevated ANGPTL7 levels were robustly associated with an increased risk of incident HF. Patients in the highest tertile had a 1.90-fold higher risk compared to the lowest (HR 1.90, 95% CI 1.47-2.45, p < 0.001). This positive association was linear (p for nonlinearity = 0.988). Time-dependent ROC analysis showed that the AUCs for ANGPTL7 in predicting 5-, 10-, and 15-year incident HF were 0.651, 0.666, and 0.670, respectively. Significant risk elevations for ANGPTL7 T3 versus T1 were consistent in both low-PRS (HR 3.20, 95% CI 1.91-5.36) and high-PRS groups (HR 1.75, 95% CI 1.14-2.69). Mechanistically, IR significantly mediated this association, with TyG-WC and METS-IR accounting for 19.4% and 9.0% of the total effect, respectively.

In T2DM patients, elevated plasma ANGPTL7 is an independent risk factor for future HF, showing a linear dose-response relationship partially mediated by IR. ANGPTL7 may represent a promising biomarker and a potential therapeutic target warranting further investigation.